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Activated growth factor receptors phosphorylate each other on tyrosine residues, and this initiates signaling by promoting interaction of the receptors with proteins that contain SH2 (Src homology 2) or PTB (phosphotyrosine-binding) domains, which recognize and preferentially bind to phosphotyrosine-containing peptides. Jones et al. conducted a genomewide quantitative analysis of such interactions that included almost every SH2 and PTB domain (more than 100 of the former and more than 40 of the latter) encoded in the human genome. They prepared protein microarrays of these domains and measured binding affinities to over 60 fluorescently tagged phosphotyrosine-containing peptides corresponding to experimentally verified sites of phosphorylation on members of the epidermal growth factor receptor (EGFR) family. After more than 77,000 such measurements, the authors were able to compare the patterns of interaction among the family members. They found 43 of 65 interactions with the EGFR, ErbB2, ErbB3, and ErbB4 that had been previously recorded in the literature, and more than 100 predicted new interactions. (One of the latter was confirmed in a cell line.) The authors found that some domains bound sites that would not have been predicted by previous estimates of consensus binding preferences and suggest that this may reflect the noncompetitive binding conditions in their assays. An intriguing possibility that may help explain the contribution of EGFR family members to cancer was also noted. The authors used the affinity measurements to predict whether binding partners would change if a receptor was present in low amounts or activated to a small extent (thus interacting primarily with partners with high affinity) or more abundant and highly active (as might occur in cancers that overexpress these proteins). ErbB2 was more promiscuous in general, with each of its binding sites binding an average of more than 17 proteins with high affinity, whereas sites on EGFR, ErbB3, and ErbB4 averaged 7, 9, and 2 high-affinity partners, respectively. When the binding threshold was lowered to approximate the effects of overexpression, EGFR and ErbB2 showed interaction with many new partners, whereas ErbB3's network of partners remained essentially the same. The authors thus speculate that EGFR and ErbB2, which are activated in some human cancers, could produce their aberrant effects in part though promiscuous interaction with binding partners not normally regulated by these proteins.